Heteroaryl substituted pyrrole modulators of metabotropic glutamate receptor-5

ABSTRACT

Pyrrole compounds substituted directly, or by a bridge, with a heteroaryl moiety containing N adjacent to the point of connection of the heteroaryl, are mGluR5 modulators useful in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, bipolar disorder and panic, as well as in the treatment of pain, circadian rhythm disorders, and other diseases.

RELATED APPLICATION DATA

This is a National filing under 35 USC 371 of PCT/US 02/40486, filedDec. 17, 2002, which claims priority from U.S. Ser. No. 60/343,262,filed Dec. 21, 2001.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to pyrrole compounds substituted witha heteroaryl moiety. In particular, this invention is directed topyrrole compounds substituted directly, or by a bridge, with aheteroaryl moiety containing N adjacent to the point of connection ofthe heteroaryl which are metabotropic glutamate receptor—subtype 5(“mGluR5”) modulators useful in the treatment of psychiatric and mooddisorders such as, for example, schizophrenia, anxiety, depression,panic, bipolar disorder, and circadian rhythm disorders, as well as inthe treatment of pain, Parkinson's disease, cognitive dysfunction,epilepsy, drug addiction, drug abuse, drug withdrawal and otherdiseases.

2. Related Background

A major excitatory neurotransmitter in the mammalian nervous system isthe glutamate molecule, which binds to neurons, thereby activating cellsurface receptors. Such surface receptors are characterized as eitherionotropic or metabotropic glutamate receptors. The metabotropicglutamate receptors (“mGluR”) are G protein-coupled receptors thatactivate intracellular second messenger systems when bound to glutamate.Activation of mGluR results in a variety of cellular responses. Inparticular, mGluR1 and mGluR5 activate phospholipase C, which isfollowed by mobilizing intracellular calcium.

Modulation of metabotropic glutamate receptor subtype 5 (mGluR5) isuseful in the treatment of diseases that affect the nervous system (seefor example W. P. J. M Spooren et al., Trends Pharmacol. Sci.,22:331-337 (2001) and references cited therein). For example, recentevidence demonstrates the involvement of mGluR5 in nociceptive processesand that modulation of mGluR5 using mGluR5-selective compounds is usefulin the treatment of various pain states, including acute, persistent andchronic pain [K Walker et al., Neuropharmacology, 40: 1-9 (2001); F.Bordi, A. Ugolini Brain Res., 871:223-233 (2001)], inflammatory pain [KWalker et al., Neuropharmacology, 40:10-19 (2001); Bhave et al. NatureNeurosci. 4:417-423 (2001)] and neuropathic pain [Dogrul et al.Neurosci. Lett. 292:115-118 (2000)].

Further evidence supports the use of modulators of mGluR5 in thetreatment of psychiatric and neurological disorders. For example,mGluR5-selective compounds such as 2-methyl-6-(phenylethynyl)-pyridine(“MPEP”) are effective in animal models of mood disorders, includinganxiety and depression [W. P. J. M Spooren et al., J. Pharmacol. Exp.Ther., 295:1267-1275 (2000); E. Tatarczynska et al, Brit. J. Pharmacol.,132:1423-1430 (2001); A. Klodzynska et al, Pol. J. Pharmacol.,132:1423-1430 (2001)]. Gene expression data from humans indicate thatmodulation of mGluR5 may be useful for the treatment of schizophrenia[T. Ohnuma et al, Mol. Brain. Res., 56:207-217 (1998); ibid, Mol. Brain.Res., 85:24-31 (2000)]. Studies have also shown a role for mGluR5, andthe potential utility of mGluR5-modulatory compounds, in the treatmentof movement disorders such as Parkinson's disease [W. P. J. M Spooren etal., Europ. J. Pharmacol. 406:403-410 (2000); H. Awad et al., J.Neurosci. 20:7871-7879 (2000); K. Ossawa et al. Neuropharmacol.41:413-420 (2001)]. Other research supports a role for mGluR5 modulationin the treatment of cognitive dysfunction [G. Riedel et al,Neuropharmacol. 39:1943-1951 (2000)], epilepsy [A. Chapman et al,Neuropharmacol. 39:1567-1574 (2000)] and neuroprotection [V. Bruno etal, Neuropharmacol. 39:2223-2230 (2000)]. Studies with mGluR5 knockoutmice and MPEP also suggest that modulation of these receptors may beuseful in the treatment of drug addiction, drug abuse and drugwithdrawal [C. Chiamulera et al. Nature Neurosci. 4:873-874 (2001)].

International Patent Publication WO 01/12627 and WO 99/26927 describeheteropolycyclic compounds and their use as metabotropic clutamatereceptor antagonists.

Compounds that include ringed systems are described by variousinvestigators as effective for a variety of therapies and utilities. Forexample, International Patent Publication No. WO 98/25883 describesketobenzamides as calpain inhibitors, European Patent Publication No. EP811610 and U.S. Pat. Nos. 5,679,712, 5,693,672 and 5,747,541 describesubstituted benzoylguanidine sodium channel blockers, and U.S. Pat. No.5,736,297 describes ring systems useful as a photosensitive composition.

However, there remains a need for novel compounds and compositions thattherapeutically inhibit mGluR5 with minimal side effects.

SUMMARY OF THE INVENTION

The present invention is directed to novel pyrrole compounds substituteddirectly, or by a bridge, with a heteroaryl moiety containing N adjacentto the point of connection of the heteroaryl, are mGluR5 modulatorsuseful in the of psychiatric and mood disorders such as, for example,schizophrenia, anxiety, depression, panic, bipolar disorder, andcircadian rhythm and sleep disorders—such as shift-work induced sleepdisorder or jet-lag, as well as in the treatment of pain, Parkinson'sdisease, cognitive dysfunction, epilepsy, drug addiction, drug abuse,drug withdrawal and other diseases. This invention also provides apharmaceutical composition which includes an effective amount of thenovel pyrrole compounds substituted with a heteroaryl moiety, and apharmaceutically acceptable carrier.

This invention further provides a method of treatment of psychiatric andmood disorders such as, for example, schizophrenia, anxiety, depression,panic, bipolar disorder, and circadian rhythm and sleep disorders—suchas shift-work induced sleep disorder or jet-lag, as well as a method oftreatment of pain, Parkinson's disease, cognitive dysfunction, epilepsy,drug addiction, drug abuse and drug withdrawal by the administration ofan effective amount of the novel pyrrole compounds substituted with aheteroaryl moiety.

DETAILED DESCRIPTION OF THE INVENTION

A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

X and Y each independently is aryl or heteroaryl wherein at least one ofX and Y is a heteroaryl with N adjacent to the position of attachment toA or B respectively;

X is optionally substituted with 1-7 independent halogen, —CN, NO₂,—C₁₋₆aklyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³,—N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴,—SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R²substituents, wherein optionally two substituents are combined to form acycloalkyl or heterocycloalkyl ring fused to X; wherein the —C₁₋₆alkylsubstituent, cycloalkyl ring, or heterocycloalkyl ring each optionallyis further substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

Y is optionally substituted with 1-7 independent halogen, —CN, NO₂,—C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkyl, —OR⁵, —NR⁵R⁶, —C(═NR⁵)NR⁶R⁷,—N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸, —NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸,—SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶, —C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶substituents, wherein optionally two substituents are combined to form acycloalkyl or heterocycloalkyl ring fused to Y; wherein the —C₁₋₆alkylsubstituent, cycloalkyl ring, or heterocycloalkyl ring each optionallyis further substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—CO₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R¹¹, R¹² and R¹³ is each independently halogen, —C₀₋₆alkyl, C₀₋₆alkoxyl,═O, ═N(C₀₋₄alkyl), or —N(C₀₋₄alkyl)(C₀₋₄alkyl), wherein optionally twoof R¹¹, R¹² and R¹³ are combined to form a cycloalkyl, heterocycloalkyl,aryl or heteroaryl ring fused to the pyrrole moiety; wherein the—C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring eachoptionally is further substituted with 1-5 independent halogen, —CN,—C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

any N may be an N-oxide; and

wherein any of the alkyl optionally is substituted with 1-9 independenthalogens.

In one aspect, the compound of this invention is represented by Formula(I) or a pharmaceutically acceptable salt thereof, wherein

X is 2-pyridyl optionally substituted with 1-4 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —(C₀₋₆alkyl), —(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —(C₃₋₇cycloalkyl), —O(aryl), (heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—CO-2alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

Y is aryl or heteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂R⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶ substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —(C₃₋₇ cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R¹¹, R¹² and R¹³ is each independently halogen, —C₀₋₆alkyl,—C₀₋₆alkoxyl, ═O, ═N(C₀₋₄alkyl), or —N(C₀₋₄alkyl)(C₀₋₄-alkyl), whereinoptionally two of R¹¹, R¹² and R¹³ are combined to form a cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),or —N(C₀₋₆alkyl)(aryl) groups;

any N may be an N-oxide; and

wherein any of the alkyl optionally is substituted with 1-9 independenthalogens.

In an embodiment of this one aspect, the compound of this invention isrepresented by Formula (I) or a pharmaceutically acceptable saltthereof, wherein

X is 2-pyridyl optionally substituted with 1-4 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

Y is phenyl optionally substituted with 1-5 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶ substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —C, C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂yl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R¹¹, R¹² and R¹³ is each independently halogen, —C₀₋₆alkyl,—C₀₋₆alkoxyl, ═O, ═N(C₀₋₄alkyl), or —N(C₀₋₄alkyl)(C₀₋₄alkyl), whereinoptionally two of R¹¹, R¹² and R¹³ are combined to form a cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),or —N(C₀₋₆alkyl)(aryl) groups;

any N may be an N-oxide; and

wherein any of the alkyl optionally is substituted with 1-9 independenthalogens.

In a second aspect, the compound of this invention is represented byFormula (I) or a pharmaceutically acceptable salt thereof, wherein

X is aryl or heteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-R⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

Y is 2-pyridyl optionally substituted with 1-4 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶ substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₁₆alkyl, —O(C₀₋₆alkyl),—O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

B is —O₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹¹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R¹¹, R¹² and R¹³ is each independently halogen, —C₀₋₆alkyl,—C₀₋₆alkoxyl, ═O, ═N(C₀₋₄alkyl), or —N(C₀₋₄alkyl)(C₀₋₄alkyl), whereinoptionally two of R¹¹, R¹² and R¹³ are combined to form a cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(CO₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),or —N(C₀₋₆alkyl)(aryl) groups;

any N may be an N-oxide; and

wherein any of the alkyl optionally is substituted with 1-9 independenthalogens.

In an embodiment of this second aspect, the compound of this inventionis represented by Formula (I) or a pharmaceutically acceptable saltthereof, wherein

X is pyridyl optionally substituted with 1-4 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

Y is 2-pyridyl optionally substituted with 14 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —O₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶ substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R¹¹, R¹² and R¹³ is each independently halogen, —C₀₋₆alkyl,—C₀₋₆alkoxyl, ═O, ═N(C₀₋₄alkyl), or —N(C₀₋₄alkyl)(C₀₋₄alkyl), whereinoptionally two of R¹¹, R¹² and R¹³ are combined to form a cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),or —N(C₀₋₆alkyl)(aryl) groups;

any N may be an N-oxide; and

wherein any of the alkyl optionally is substituted with 1-9 independenthalogens.

In a third aspect the compound of this invention is represented byFormula (I) or a pharmaceutically acceptable salt thereof, wherein

X is phenyl optionally substituted with 1-5 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

Y is aryl or heteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶ substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —C, —C₁₋₁₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₁₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R¹¹, R¹² and R¹³ is each independently halogen, —C₀₋₆alkyl,—C₀₋₆alkoxyl, ═O, ═N(C₀₋₄alkyl), or —N(C₀₋₄alkyl)(C₀₋₄alkyl), whereinoptionally two of R¹¹, R¹² and R¹³ are combined to form a cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —CN, C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),or —N(C₀₋₆alkyl)(aryl) groups;

any N may be an N-oxide; and

wherein any of the alkyl optionally is substituted with 1-9 independenthalogens.

In an embodiment of this third aspect, the compound of this invention isrepresented by Formula (I) or a pharmaceutically acceptable saltthereof, wherein

X is phenyl optionally substituted with 1-5 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³,—N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴,—SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R²substituents, wherein optionally two substituents are combined to form acycloalkyl or heterocycloalkyl ring fused to X; wherein the —C₁₋₆alkylsubstituent, cycloalkyl ring, or heterocycloalkyl ring each optionallyis further substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl-,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —C, —C₁₋₆alkyl, —O(C₀₋₆alkyl),—O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

Y is 2-pyridyl optionally substituted with 1-4 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶ substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alky-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-, —CO₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆-alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R¹¹, R¹² and R¹³ is each independently halogen, —C₀₋₆alkyl,—C₀₋₆alkoxyl, ═O, ═N(C₀₋₄alkyl), or —N(C₀₋₄alkyl)(C₀₋₄alkyl), whereinoptionally two of R¹¹, R¹² and R¹³ are combined to form a cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),or —N(C₀₋₆alkyl)(aryl) groups;

any N may be an N-oxide; and

wherein any of the alkyl optionally is substituted with 1-9 independenthalogens.

In a fourth aspect, the compound of this invention is represented byFormula (I) or a pharmaceutically acceptable salt thereof, wherein

X is aryl or heteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

Y is 1,3-thiazol-2-yl optionally substituted with 1-2 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —R⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶ substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO²—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R¹¹, R¹² and R¹³ is each independently halogen, —C₀₋₆alkyl,—C₀₋₆alkoxyl, ═O, ═N(C₀₋₄alkyl), or —N(C₀₋₄alkyl)(C₀₋₄alkyl), whereinoptionally two of R¹¹, R¹² and R¹³ are combined to form a cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),or —N(C₀₋₆alkyl)(aryl) groups;

any N may be an N-oxide; and

wherein any of the alkyl optionally is substituted with 1-9 independenthalogens.

In an embodiment of this fourth aspect, the compound of this inventionis represented by Formula (I) or a pharmaceutically acceptable saltthereof, wherein

X is phenyl optionally substituted with 1-5 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

Y is 1,3-thiazol-2-yl optionally substituted with 1-2 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶ substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₁₆alkyl, —O(C₀₋₆alkyl),—O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R¹¹, R¹² and R¹³ is each independently halogen, —C₀₋₆alkyl,—C₀₋₆alkoxyl, ═O, ═N(C₀₋₄alkyl), or —N(C₀₋₄alkyl)(C₀₋₄alkyl), whereinoptionally two of R¹¹, R¹² and R¹³ are combined to form a cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),or —N(C₀₋₆alkyl)(aryl) groups;

any N may be an N-oxide; and

wherein any of the alkyl optionally is substituted with 1-9 independenthalogens.

In a fifth aspect, the compound of this invention is represented byFormula (I) or a pharmaceutically acceptable salt thereof, wherein

X is aryl or heteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(eteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

Y is pyrazolyl optionally substituted with 1-3 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶,—C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸,—NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶,—C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶ substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R¹¹, R¹² and R¹³ is each independently halogen, —C₀₋₆alkyl,—C₀₋₆alkoxyl, ═O, ═N(C₀₋₄alkyl), or —N(C₀₋₄-alkyl)(C₀₋₄alkyl), whereinoptionally two of R¹¹, R¹² and R¹³ are combined to form a cycloalkyl,heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloakyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),or —N(C₀₋₆alkyl)(aryl) groups;

any N may be an N-oxide; and

wherein any of the alkyl optionally is substituted with 1-9 independenthalogens.

In an embodiment of this fifth aspect, the compound of this invention isrepresented by Formula (I) or a pharmaceutically acceptable saltthereof, wherein

X is phenyl optionally substituted with 1-5 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³,—N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴,—SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R²substituents, wherein optionally two substituents are combined to form acycloalkyl or heterocycloalkyl ring fused to X; wherein the —C₁₋₆alkylsubstituent, cycloalkyl ring, or heterocycloalkyl ring each optionallyis further substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R¹, R², and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁴ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

A is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂—C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

Y is pyrazolyl optionally substituted with 1-2 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkyl, —OR⁵, —NR⁵R⁶, —C(═NR⁵)NR⁶R⁷,—N(═NR⁵)NR⁶R⁷, —NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸, —NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸,—SO₂R⁸, —SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶, —C(═NR⁵)R⁶, or —C(═NOR⁵)R⁶substituents, wherein optionally two substituents are combined to form acycloalkyl or heterocycloalkyl ring fused to Y; wherein the —C₁₋₆alkylsubstituent, cycloalkyl ring, or heterocycloalkyl ring each optionallyis further substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

R⁵, R⁶, and R⁷ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R⁸ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; optionallysubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents;

B is —C₀₋₄alkyl, —C₀₋₂alkyl-SO—C₀₋₂alkyl-, —CO₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₂alkyl-NR¹⁰SO₂C₀₋₂alkyl- or -heteroC₀₋₄alkyl;

R⁹ and R¹⁰ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; any of which is optionally substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), —N(C₀₋₆alkyl)(aryl) substituents;

R¹¹, R¹² and R¹³ is each independently halogen, —C₀₋₆alkyl, C₀₋₆alkoxyl,═O, ═N(C₀₋₄alkyl), or —N(C₀₋₄alkyl)(C₀₋₄alkyl), wherein optionally twoof R¹¹, R¹² and R¹³ are combined to form a cycloalkyl, heterocycloalkyl,aryl or heteroaryl ring fused to the pyrrole moiety; wherein the—C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring eachoptionally is further substituted with 1-5 independent halogen, —C,—C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups;

any N may be an N-oxide; and

wherein any of the alkyl optionally is substituted with 1-9 independenthalogens.

Thus, the compound of this invention is represented by Formula (I) or apharmaceutically acceptable salt thereof, wherein

X is 2-pyridyl optionally substituted with 1-4 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups.

Further, the compound of this invention is represented by Formula (I) ora pharmaceutically acceptable salt thereof, wherein

X is 2-pyridyl optionally substituted with 1-4 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups; and

Y is phenyl optionally substituted with 1-5 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₁₆alkyl, —O(C₀₋₆alkyl),—O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups.

Still further, the compound of this invention is represented by Formula(I) or a pharmaceutically acceptable salt thereof, wherein

X is aryl or heteroaryl optionally substituted with 1-7 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴—SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups; and

Y is 2-pyridyl optionally substituted with 1-4 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —COR₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups.

Even further, the compound of this invention is represented by Formula(I) or a pharmaceutically acceptable salt thereof, wherein

X is pyridyl optionally substituted with 1-4 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups; and

Y is 2-pyridyl optionally substituted with 14 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(—NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups.

Still further, the compound of this invention is represented by Formula(I) or a pharmaceutically acceptable salt thereof, wherein

X is phenyl optionally substituted with 1-5 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups.

Even further, the compound of this invention is represented by Formula(I) or a pharmaceutically acceptable salt thereof, wherein

X is phenyl optionally substituted with 1-5 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups; and

Y is 2-pyridyl optionally substituted with 1-4 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups.

And, the compound of this invention is represented by Formula (I) or apharmaceutically acceptable salt thereof, wherein

Y is 1,3-thiazol-2-yl optionally substituted with 1-2 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(eteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups.

Further, the compound of this invention is represented by Formula (I) ora pharmaceutically acceptable salt thereof, wherein

Y is 1,3-thiazol-2-yl optionally substituted with 1-2 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(—NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups; and

X is phenyl optionally substituted with 1-5 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),-—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups.

And, the compound of this invention is represented by Formula (I) or apharmaceutically acceptable salt thereof, wherein

Y is pyrazolyl optionally substituted with 1-3 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³,—N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴,SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R²substituents, wherein optionally two substituents are combined to form acycloalkyl or heterocycloalkyl ring fused to Y; wherein the —C₁₋₆alkylsubstituent, cycloalkyl ring, or heterocycloalkyl ring each optionallyis further substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups.

Further, the compound of this invention is represented by Formula (I) ora pharmaceutically acceptable salt thereof, wherein

Y is pyrazolyl optionally substituted with 1-3 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups; and

X is phenyl optionally substituted with 1-5 independent halogen, —CN,NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³,—N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴,—SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R²substituents, wherein optionally two substituents are combined to form acycloalkyl or heterocycloalkyl ring fused to X; wherein the —C₁₋₆alkylsubstituent, cycloalkyl ring, or heterocycloalkyl ring each optionallyis further substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups.

As used herein, “alkyl” as well as other groups having the prefix “alk”such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like,means carbon chains which may be linear or branched or combinationsthereof. Examples of alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and thelike. “Alkenyl”, “alkynyl” and other like terms include carbon chainscontaining at least one unsaturated C—C bond.

The term “cycloalkyl” means carbocycles containing no heteroatoms, andincludes mono-, bi- and tricyclic saturated carbocycles, as well asfused ring systems. Such fused ring systems can include one ring that ispartially or fully unsaturated such as a benzene ring to form fused ringsystems such as benzofused carbocycles. Cycloalkyl includes such fusedring systems as spirofused ring systems. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene,adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphalene andthe like. Similarly, “cycloalkenyl” means carbocycles containing noheteroatoms and at least one non-aromatic C—C double bond, and includemono-, bi- and tricyclic partially saturated carbocycles, as well asbenzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl,indenyl, and the like.

The term “aryl” means an aromatic substituent which is a single ring ormultiple rings fused together. When formed of multiple rings, at leastone of the constituent rings is aromatic. The preferred arylsubstituents are phenyl and naphthyl groups.

The term “cycloalkyloxy” unless specifically stated otherwise includes acycloalkyl group connected by a short C₁₋₂alkyl length to the oxyconnecting atom.

The term “C₀₋₆alkyl” includes alkyls containing 6, 5, 4, 3, 2, 1, or nocarbon atoms. An alkyl with no carbon atoms is a hydrogen atomsubstituent when the alkyl is a terminal group and is a direct bond whenthe alkyl is a bridging group.

The term “hetero” unless specifically stated otherwise includes one ormore O, S, or N atoms. For example, heterocycloalkyl and heteroarylinclude ring systems that contain one or more O, S, or N atoms in thering, including mixtures of such atoms. The hetero atoms replace ringcarbon atoms. Thus, for example, a heterocycloC₅alkyl is a five-memberring containing from 4 to no carbon atoms. Examples of heteroarylsinclude pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl,pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl,benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl,benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl,imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, andtetrazolyl. Examples of heterocycloalkyls include azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.

The term “heteroC₀₋₄alkyl” means a heteroalkyl containing 3, 2, 1, or nocarbon atoms. However, at least one heteroatom must be present. Thus, asan example, a heteroC₀₋₄alkyl having no carbon atoms but one N atomwould be a —NH— if a bridging group and a —NH₂ if a terminal group.Analogous bridging or terminal groups are clear for an O or Sheteroatom.

The term “amine” unless specifically stated otherwise includes primary,secondary and tertiary amines substituted with C₀₋₆alkyl.

The term “carbonyl” unless specifically stated otherwise includes aC₀₋₆alkyl substituent group when the carbonyl is terminal.

The term “halogen” includes fluorine, chlorine, bromine and iodineatoms.

The term “optionally substituted” is intended to include bothsubstituted and unsubstituted. Thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring. Further,optionally substituted multiple moieties such as, for example, alkylarylare intended to mean that the aryl and the aryl groups are optionallysubstituted. If only one of the multiple moieties is optionallysubstituted then it will be specifically recited such as “an alkylaryl,the aryl optionally substituted with halogen or hydroxyl.”

Compounds described herein contain one or more double bonds and may thusgive rise to cis/trans isomers as well as other conformational isomers.The present invention includes all such possible isomers as well asmixtures of such isomers.

Compounds described herein can contain one or more asymmetric centersand may thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Particularly preferred are citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, and tartaric acids.

The pharmaceutical compositions of the present invention comprise acompound represented by Formula I (or pharmaceutically acceptable saltsthereof) as an active ingredient, a pharmaceutically acceptable carrierand optionally other therapeutic ingredients or adjuvants. Suchadditional therapeutic ingredients include, for example, i) opiateagonists or antagonists, ii) calcium channel antagonists, iii) 5HTreceptor agonists or antagonists iv) sodium channel antagonists, v) NMDAreceptor agonists or antagonists, vi) COX-2 selective inhibitors, vii)NK1 antagonists, viii) non-steroidal anti-inflammatory drugs (“NSAID”),ix) GABA-A receptor modulators, x) dopamine agonists or antagonists, xi)selective serotonin reuptake inhibitors (“SSRI”) and/or selectiveserotonin and norepinephrine reuptake inhibitors (“SSNRI”), xii)tricyclic antidepressant drugs, xiv) norepinephrine modulators, xv)L-DOPA, xvi) buspirone, xvii) lithium, xviii) valproate, ixx) neurontin(gabapentin), xx) olanzapine, xxi) nicotinic agonists or antagonistsincluding nicotine, xxii) muscarinic agonists or antagonists, xxiii)heroin substituting drugs such as methadone, levo-alpha-acetylmethadol,buprenorphine and naltrexone, and xxiv) disulfirm and acamprosate. Thecompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

Creams, ointments, jellies, solutions, or suspensions containing thecompound of Formula I can be employed for topical use. Mouth washes andgargles are included within the scope of topical use for the purposes ofthis invention.

Dosage levels from about 0.01 mg/kg to about 140 mg/kg of body weightper day are useful in the treatment of psychiatric and mood disorderssuch as, for example, schizophrenia, anxiety, depression, panic, bipolardisorder, and circadian rhythm and sleep disorders—such as shift-workinduced sleep disorder or jet-lag, as well as being useful in thetreatment of pain which are responsive to mGluR5 inhibition, oralternatively about 0.5 mg to about 7 g per patient per day. Forexample, schizophrenia, anxiety, depression, panic, bipolar disorder,and circadian rhythm and sleep disorders—such as shift-work inducedsleep disorder or jet-lag, may be effectively treated by theadministration of from about 0.01 mg to 75 mg of the compound perkilogram of body weight per day, or alternatively about 0.5 mg to about3.5 g per patient per day. Pain may be effectively treated by theadministration of from about 0.01 mg to 125 mg of the compound perkilogram of body weight per day, or alternatively about 0.5 mg to about5.5 g per patient per day. Further, it is understood that the mGluR5inhibiting compounds of this invention can be administered atprophylactically effective dosage levels to prevent the above-recitedconditions.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration to humans mayconveniently contain from about 0.5 mg to about 5 g of active agent,compounded with an appropriate and convenient amount of carrier materialwhich may vary from about 5 to about 95 percent of the totalcomposition. Unit dosage forms will generally contain between from about1 mg to about 1000 mg of the active ingredient, typically 25 mg, 50 mg,100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

In practice, the compounds represented by Formula I, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compound represented byFormula I, or pharmaceutically acceptable salts thereof, may also beadministered by controlled release means and/or delivery devices. Thecompositions may be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of Formula I. The compounds of Formula I, orpharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.1 mg to about 500 mg of theactive ingredient and each cachet or capsule preferably containing fromabout 0.1 mg to about 500 mg of the active ingredient. Thus, a tablet,cachet, or capsule conveniently contains 0.1 mg, 1 mg, 5 mg, 25 mg, 50mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredienttaken one or two tablets, cachets, or capsules, once, twice, or threetimes daily.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol),vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or pharmaceutically acceptable saltsthereof, via conventional processing methods. As an example, a cream orointment is prepared by mixing hydrophilic material and water, togetherwith about 5 wt % to about 10 wt % of the compound, to produce a creamor ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

The compounds and pharmaceutical compositions of this invention havebeen found to exhibit biological activity as mGluR5 inhibitors.Accordingly, another aspect of the invention is the treatment in mammalsof, for example, schizophrenia, anxiety, depression, panic, bipolardisorder, and circadian rhythm and sleep disorders—such as shift-workinduced sleep disorder or jet-lag, pain, Parkinson's disease, cognitivedysfunction, epilepsy, drug addiction, drug abuse and drugwithdrawal—maladies that are amenable to amelioration through inhibitionof mGluR5—by the administration of an effective amount of the compoundsof this invention. The term “mammals” includes humans, as well as otheranimals such as, for example, dogs, cats, horses, Figs, and cattle.Accordingly, it is understood that the treatment of mammals other thanhumans is the treatment of clinical correlating afflictions to thoseabove recited examples that are human afflictions.

Further, as described above, the compound of this invention can beutilized in combination with other therapeutic compounds. In particular,the combinations of the mGluR5 inhibiting compound of this invention canbe advantageously used in combination with i) opiate agonists orantagonists, ii) calcium channel antagonists, iii) 5HT receptor agonistsor antagonists iv) sodium channel antagonists, v) NMDA receptor agonistsor antagonists, vi) COX-2 selective inhibitors, vii) NK1 antagonists,viii) non-steroidal anti-inflammatory drugs (“NSAID”), ix) GABA-Areceptor modulators, x) dopamine agonists or antagonists, xi) selectiveserotonin reuptake inhibitors (“SSRI”) and/or selective serotonin andnorepinephrine reuptake inhibitors (“SSNRI”), xii) tricyclicantidepressant drugs, xiii) norepinephrine modulators, xiv) L-DOPA, xv)buspirone, xvi) lithium, xvii) valproate, xviii) neurontin (gabapentin),xix) olanzapine, xx) nicotinic agonists or antagonists includingnicotine, xxi) muscarinic agonists or antagonists, xxii) heroinsubstituting drugs such as methadone, levo-alpha-acetylmethadol,buprenorphine and naltrexone, and xxiii) disulfiram and acamprosate.

The abbreviations used herein have the following tabulated meanings.Abbreviations not tabulated below have their meanings as commonly usedunless specifically stated otherwise.

Ac acetyl AIBN 2,2′-azobis(isobutyronitrile) BINAP 1,1′-bi-2-naphthol Bnbenzyl CAMP cyclic adenosine-3′,5′-monophosphate DAST(diethylamino)sulfur trifluoride DEAD diethyl azodicarboxylate DBU1,8-diazabicyclo[5.4.0]undec-7-ene DIBAL diisobutylaluminum hydride DMAP4-(dimethylamino)pyridine DMF N,N-dimethylformamide dppf1,1′-bis(diphenylphosphino)-ferrocene EDCI1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Et₃Ntriethylamine GST glutathione transferase HMDS hexamethyldisilazide LDAlithium diisopropylamide m-CPBA metachloroperbenzoic acid MMPPmonoperoxyphthalic acid MPPM monoperoxyphthalic acid, magnesium salt6H₂O Ms methanesulfonyl = mesyl = SO₂Me Ms0 methanesulfonate = mesylateNBS N-bromo succinimide NSAID non-steroidal anti-inflammatory drug o-Tolortho-tolyl OXONE ® 2KHSO₅.KHSO₄.K₂SO₄ PCC pyridinium chlorochromatePd₂(dba)₃ Bis(dibenzylideneacetone) palladium(0) PDC pyridiniumdichromate PDE Phosphodiesterase Ph Phenyl Phe Benzenediyl PMBpara-methoxybenzyl Pye Pyridinediyl r.t. room temperature Rac. RacemicSAM aminosulfonyl or sulfonamide or SO₂NH₂ SEM2-(trimethylsilyl)ethoxymethoxy SPA scintillation proximity assay TBAFtetra-n-butylammonium fluoride Th 2- or 3-thienyl TFA trifluoroaceticacid TFAA trifluoroacetic acid anhydride THF Tetrahydrofuran ThiThiophenediyl TLC thin layer chromatography TMS-CN trimethylsilylcyanide TMSI trimethylsilyl iodide Tz 1H (or 2H)-tetrazol-5-yl XANTPHOS4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H- xanthene C₃H₅ Allyl

ALKYL GROUP ABBREVIATIONS Me = Methyl Et = ethyl n-Pr = normal propyli-Pr = isopropyl n-Bu = normal butyl i-Bu = isobutyl s-Bu = secondarybutyl t-Bu = tertiary butyl c-Pr = cyclopropyl c-Bu = cyclobutyl c-Pen =cyclopentyl c-Hex = cyclohexyl

Assays Demonstrating Biological Activity

The compounds of this invention were tested against the hmGluR5areceptor stably expressed in mouse fibroblast Ltk⁻ cells (thehmGluR5a/L38-20 cell line) and activity was detected by changes in[Ca⁺⁺]_(i), measured using the fluorescent Ca⁺⁺-sensitive dye, fura-2.InsP assays were performed in mouse fibroblast Ltk⁻ cells (LM5a cellline) stably expressing hmGluR5a. The assays described in InternationalPatent Publication WO 0116121 can be used.

Calcium Flux Assay

The activity of compounds was examined against the hmGluR5a receptorstably expressed in mouse fibroblast Ltk-cells (the hmGluR5a/L38 cellline). See generally Daggett et al., Neuropharmacology 34:871-886(1995). Receptor activity was detected by changes in intracellularcalcium ([Ca²⁺ ]_(i)) measured using the fluorescent calcium-sensitivedye, fura-2. The hmGluR5a/L38-20 cells were plated onto 96-well plates,and loaded with 3 μM fura-2 for 1 h. Unincorporated dye was washed fromthe cells, and the cell plate was transferred to a 96-channelfluorimeter (SIBIA-SAIC, La Jolla, Calif.) which is integrated into afully automated plate handling and liquid delivery system. Cells wereexcited at 350 and 385 nm with a xenon source combined with opticalfilters. Emitted light was collected from the sample through a dichroicmirror and a 510 nm interference filter and directed into a cooled CCDcamera (Princeton Instruments). Image pairs were captured approximatelyevery 1 s, and ratio images were generated after background subtraction.After a basal reading of 20 s, an EC₈₀ concentration of glutamate (10μM) was added to the well, and the response evaluated for another 60 s.The glutamate-evoked increase in [Ca′]_(i) in the presence of thescreening compound was compared to the response of glutamate alone (thepositive control).

Phosphatidylinositol Hydrolysis (PI) Assays

Inositolphosphate assays were performed as described by Berridge et al.[Berridge et al, Biochem. J. 206: 587-5950 (1982); and Nakajima et al.,J. Biol. Chem. 267:2437-2442 (1992)] with slight modifications. Mousefibroblast Ltk cells expressing hmGluR5 (hmGluR5/L38-20 cells) wereseeded in 24-well plates at a density of 8×105 cells/well. One μCi of[³H]-inositol (Amersham PT6-271; Arlington Heights, Ill.; specificactivity=17.7 Ci/mmol) was added to each well and incubated for 16 h at37° C. Cells were washed twice and incubated for 45 min in 0.5 mL ofstandard Hepes buffered saline buffer (HBS; 125 mM NaCl, 5 mM KCL 0.62mM MgSO₄, 1.8 mM CaCl₂, 20 mM HEPES, 6 mM glucose, pH to 7.4). The cellswere washed with HBS containing 10 mM LiCl, and 400 μL buffer added toeach well. Cells were incubated at 37° C. for 20 min. For testing, 50 μLof 10× compounds used in the practice of the invention (made in HBS/LiCl(100 mM)) was added and incubated for 10 minutes. Cells were activatedby the addition of 10 μM glutamate, and the plates left for 1 hour at37° C. The incubations were terminated by the addition of 1 mL ice-coldmethanol to each well. In order to isolate inositol phosphates (IPs),the cells were scraped from wells, and placed in numbered glass testtubes. One mL of chloroform was added to each tube, the tubes weremixed, and the phases separated by centrifugation. IPs were separated onDowex anion exchange columns (AG 1-X8 100-200 mesh formate form). Theupper aqueous layer (750 μL) was added to the Dowex columns, and thecolumns eluted with 3 mL of distilled water. The eluents were discarded,and the columns were washed with 10 mLs of 60 mM ammonium formate/5 mMBorax, which was also discarded as waste. Finally, the columns wereeluted with 4 mL of 800 mM ammonium formate/0.1M formic acid, and thesamples collected in scintillation vials. Scintillant was added to eachvial, and the vials shaken, and counted in a scintillation counter after2 hours. Phosphatidylinositol hydrolysis in cells treated with certainexemplary compounds was compared to phosphatidylinositol hydrolysis incells treated with the agonist alone in the absence of compound.

The compounds of this application have mGluR5 inhibitory activity asshown by IC₅₀ values of less than 10 μM in the calcium flux assay orinhibition of >50% at a concentration of 100 μM in the PI assay.Preferably, the compounds should have IC₅₀ values of less than 1 μM inthe calcium flux assay and IC₅₀ values of less than 10 μM in the PIassay. Even more preferably, the compounds should have IC₅₀ values ofless than 100 nM in the calcium flux assay and IC₅₀ values of less than1 μM in the PI assay.

Examples 1-22 have mGluR5 inhibitory activity as shown by IC₅₀ values of10 μM or better in the calcium flux assay and/or inhibition of >50% at100 μM concentration in the PI assay.

The examples that follow are intended as an illustration of certainpreferred embodiments of the invention and no limitation of theinvention is implied.

Unless specifically stated otherwise, the experimental procedures wereperformed under the following conditions. All operations were carriedout at room or ambient temperature—that is, at a temperature in therange of 18-25° C. Evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) witha bath temperature of up to 60° C. The course of reactions was followedby thin layer chromatography (TLC) and reaction times are given forillustration only. Melting points are uncorrected and ‘d’ indicatesdecomposition. The melting points given are those obtained for thematerials prepared as described. Polymorphism may result in isolation ofmaterials with different melting points in some preparations. Thestructure and purity of all final products were assured by at least oneof the following techniques: TLC, mass spectrometry, nuclear magneticresonance (NMR) spectrometry or microanalytical data. When given, yieldsare for illustration only. When given, NMR data is in the form of delta(δ) values for major diagnostic protons, given in parts per million(ppm) relative to tetramethylsilane (CMS) as internal standard,determined at 300 MHz, 400 MHz or 500 MHz using the indicated solvent.Conventional abbreviations used for signal shape are: s. singlet; d.doublet; t. triplet; m. multiplet; br. broad; etc. In addition, “Ar”signifies an aromatic signal. Chemical symbols have their usualmeanings; the following abbreviations are used: v (volume), w (weight),b.p. (boiling point), m.p. (melting point), L (liter(s)), mL(milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol(millimoles), eq (equivalent(s)).

Methods of Synthesis

Compounds of the present invention can be prepared according to thefollowing methods. The substituents are the same as in Formula I exceptwhere defined otherwise, or apparent to one in the art.

In accordance with another embodiment of the present invention, thereare provided methods for the preparation of heteroaryl-substitutedpyrrole compounds as described above. For example, many of theheterocyclic compounds described above can be prepared using syntheticchemistry techniques well known in the art (see ComprehensiveHeterocyclic Chemistry, Katritzky, A. R. and Rees, C. W. eds., PergamonPress, Oxford, 1984) from a heteoaryl-substituted pyrrole of Formula(I).

In Schemes 1 to 5 below, X and Y are as defined above. Other variablesare understood by one in the art by the context in which they are used.

Thus in Scheme 1, ring system X containing an aniline moiety (preparedusing synthetic chemistry techniques well known in the art) is reactedwith a 1,4-dicarbonyl or its equivalent in a suitable solvent (e.g.EtOH, THF, DME, DMF etc.) at a temperature between 30° C. to 150° C. for1 to 18 h to form a substituted pyrrole. In turn, the 3-position of thepyrrole is derivatized with a functional group A, such as a halogen ortrifiuoromethanesulfonate and the like, which is capable of undergoing ametal-catalyzed cross-coupling reaction. For example, the group A may bea bromine atom which may be installed using bromotrimethylsilane (seefor example Pagnoni, U. G.; Pinetti, A. J. Heterocycl. Chem. 1993, 30,617-621).

In turn, the derivatized pyrrole is reacted with a moiety Y undermetal-catalyzed cross-coupling conditions (Scheme 2) where E is ametallic or metalloid species such as B(OR)₂, Li, MgHal, SnR₃, ZnHal,SiR₃ and the like which is capable of undergoing a metal-catalyzedcross-coupling reaction. The coupling may be promoted by a homogeneouscatalyst such as Pd(PPh₃)₄, or by a heterogeneous catalyst such as Pd oncarbon in a suitable solvent (e.g. THF, DME, toluene, MeCN, DMF, H₂Oetc.). Typically a base, such as K₂CO₃, NEt₃, and the like, will also bepresent in the reaction mixture. Other promoters may also be used suchas CsF. The coupling reaction is typically allowed to proceed byallowing the reaction temperature to warm slowly from about 0° C. up tort over a period of several hours. The reaction mixture is thenmaintained at rt, or heated to a temperature anywhere between 30° C. to150° C. The reaction mixture is then maintained at a suitabletemperature for a time in the range of about 4 up to 48 h, with about 18h typically being sufficient (see for example Miyaura, N.; Suzuki, A.Chem. Rev. 1995, 95, 2457-2483). The product from the reaction can beisolated and purified employing standard techniques, such as solventextraction, chromatography, crystallization, distillation and the like.Another embodiment of the present invention is illustrated in Scheme 3.

Thus, the free ring nitrogen in an optionally substituted pyrrole(prepared using synthetic chemistry techniques well known in the art) isprotected with a group P, where P may be a trialkyl- or triaryl silane,arylsulfonyl or alkyl carbamate protecting group and the like. In turn,the 3-position of the pyrrole is derivatized with a functional group A,such as a halogen or trifluoromethanesulfonate and the like, which iscapable of undergoing a metal-catalyzed cross-coupling reaction. Forexample, the group A may be an iodine which maybe installed usingmolecular iodine and mercuric acetate (see for example Bray, B. L. etal. J. Org. Chem. 1990, 55, 6317-6328).

In turn, the derivatized pyrrole is reacted with a moiety Y undermetal-catalyzed cross-coupling conditions (Scheme 4) where E is ametallic or metalloid species such as B(OR)₂, ZnHal, Li, MgHal, SnR₃,SiR₃ and the like which is capable of undergoing a metal-catalyzedcross-coupling reaction. The coupling may be promoted by a homogeneouscatalyst such as Pd(PPh₃)₄, or by a heterogeneous catalyst such as Pd oncarbon in a suitable solvent (e.g. THF, DME, toluene, MeCN, DMF, H₂Oetc.). If required a base, such as K₂CO₃, NEt₃, and the like, will alsobe present in the reaction mixture. Other promoters may also be usedsuch as CsF. The coupling reaction is typically allowed to proceed byallowing the reaction temperature to warm slowly from about 0° C. up tort over a period of several hours. The reaction mixture is thenmaintained at rt, or heated to a temperature anywhere between 30° C. to150° C. The reaction mixture is then maintained at a suitabletemperature for a time in the range of about 4 up to 48 h, with about 18h typically being sufficient (see for example: Miyaura, N.; Suzuki, A.Chem. Rev. 1995, 95, 2457-2483 or Negishi, E.; Liu, F. Palladium orNickel catalyzed Cross-coupling with Organometals Containing Zinc,Magnesium, Aluminium and Zirconium. In Metal-catalyzed Cross-couplingReactions Diederich, F.; Stang, P. J. Eds. Wiley, Weinheim, Germany,1998; pp1-42). The product from the reaction can be isolated andpurified employing standard techniques, such as solvent extraction,chromatography, crystallization, distillation and the like.

As shown in Scheme 5, the pyrrole may then be coupled with a species Xsubstituted with a group B. B may be a good aryl leaving group such asP, and X is electron deficient or has one or more electron withdrawingsubstituents (e.g. NO₂, CN etc.), the coupling reaction may be effectedthermally in a temperature range of about 60° C. up to about 250° C.Typically, this reaction is carried out in the presence of base (e.g.pyridine, NEt₃, Cs₂CO₃, K₂CO₃ etc.) in a suitable solvent, such as DMSO,DMF, DMA H₂O and the like, and takes from 1 h up to about 72 h with 18 htypically being sufficient (see for example Russell, S. S.; Jahangir;Synth. Commun. 1994, 24, 123-130).

Alternatively, B may be a good leaving group capable of undergoing ametal-catalyzed cross-coupling reaction such as a halogen ortrifluoromethanesulfonate and the like. Typically, the reaction iscarried out using catalytic amounts of a copper (I) salt together with adiamine ligand and in the presence of a suitable base (e.g. K₃PO₄,Cs₂CO₃, K₂CO₃ etc.) in a suitable solvent, such as Dioxane, DMSO, DMA,DMF (see for example Klapers, A.; Antilla, J. C.; Huang, X.; Buchwald,S. L J. Am. Chem Soc. 2001, in press).

In addition, many of the heterocyclic compounds described above can beprepared using other synthetic chemistry techniques well known in theart (see Comprehensive Heterocyclic Chemistry, Katritzky, A. R. andRees, C. W. eds., Pergamon Press, Oxford, 1984) and references citedthere within.

COMPOUND 1 Synthesis of 2-(3-bromo-1H-pyrrol-1-yl)pyridine

Bromotrimethylsilane (10.9 mL, 84 mmol) was added to DMSO (5.7 mL, 84mmol) in MeCN (200 mL) at 0° C. After stirring for 10 min,2-(1H-pyrrol-1-yl)pyridine (10 g, 70 mmol) in MeCN (50 mL) was added.The reaction mixture was stirred at 0° C. and allowed to reach rt over 3h. H₂O (150 mL) and EtOAc (150 mL) were added and the reaction mixturewas shaken, the EtOAc layer was separated and the aqueous layer shakenwith EtOAc (3×150 mL). The combine organic layers were dried over Na₂SO₄and concentrated to a brown oil. LCMS indicated good conversion to2-(3-bromo-1H-pyrrol-1-yl)pyridine and this was used without furtherpurification. (MS (ESI) 224 (M+H)⁺.

EXAMPLE 1 Synthesis of 3-(1-pyridin-2-yl-1H-pyrrol-3-yl)benzonitrile

2-(3-Bromo-1H-pyrrol-1-yl)pyridine (1.34 g, 2 mmol),3-cyanophenylboronic acid (0.59 g, 4 mmol), Pd(PPh₃)₄ (116 mg, 0.1 mmol)and potassium carbonate (560 mg, 4 mmol) were dissolved in a mixture ofDME (18 mL) and H₂O (2 mL) and degassed for 15 min with Ar (g). Thereaction mixture was then heated at 84° C. for 18 h. At this time, afurther 0.25 eq. of 3-cyanophenylboronic acid (0.15 g, 1 mmol) was addedand heating was continued. After a total of 42 h, the reaction mixturewas cooled to rt, H₂O (40 mL) and EtOAc (40 mL) were added and thereaction mixture shaken, the EtOAc layer was separated and the aqueouslayer shaken with EtOAc (2×30 mL). The combined organic layers weredried over Na₂SO₄ and concentrated to a yellow oil. This was purified byliquid chromatography on silica gel eluting with EtOAc:hexane (3:7) toafford a white waxy solid that was further purified by liquidchromatography on silica gel eluting with dichloromethane to afford3-(1-pyridin-2-yl-1H-pyrrol-3-yl)benzonitrile as a colorless oil. ¹H NMR(CD₃Cl, 300 MHz) δ 8.49-8.52 (1H, m), 7.66 (1H, ddd), 7.47-7.51 (2H, m),7.33-7.39 (3H, m), 7.24 (1H, ddd), 6.91 (1H, d), 6.51-6.52 (1H, m), 6.43(1H, dd). MS (ESI) 246 (M+H)⁺.

EXAMPLE 2 Synthesis of 2-[3-(3-chlorophenyl)-1H-pyrrol-1-yl]pyridine

2-(3-Bromo-1H-pyrrol-1-yl)pyridine (1.34 g, 2 mmol),3-chlorophenylboronic acid (0.62 g, 4 mmol), Pd(PPh₃)₄ (116 mg, 0.1mmol) and potassium carbonate (560 mg, 4 mmol) were dissolved in amixture of DME (18 mL) and H₂O (2 mL) and degassed for 15 min with Ar(g). The reaction mixture was then heated at 84° C. for 18 h. At thistime, a further 0.25 eq. of 3-chlorophenylboronic acid (0.16 g, 1 mmol)was added and heating was continued. After a total of 42 h, the reactionmixture was cooled to rt, H₂O (40 mL) and EtOAc (40 mL) were added andthe reaction mixture shaken, the EtOAc layer was separated and theaqueous layer shaken with EtOAc (2×30 mL). The combined organic layerswere dried over Na₂SO₄ and concentrated to a yellow oil. This waspurified by liquid chromatography on silica gel eluting withEtOAc:hexane (3:7) to afford a white solid that was further purified bypreparative HPLC to afford 2-[3-(3-chlorophenyl)-1H-pyrrol-1-yl]pyridineas a white solid. ¹H NMR (CD₃Cl, 300 MHz) δ 8.52-8.54 (1H, m), 7.61 (1H,ddd), 7.35-7.37 (1H, m), 7.28 (1H, s), 7.15-7.24 (3H, m), 6.99 (1H,ddd), 6.86 (1H, d), 6.47-6.48 (1H, m), 6.41 (1H, dd).). MS (ESI) 255(M+H)⁺.

EXAMPLE 3 Synthesis of 2-[3-(3-methoxyphenyl)-1H-pyrrol-1-yl]pyridine

2-(3-Bromo-1H-pyrrol-1-yl)pyridine (1.34 g, 2 mmol),3-methoxyphenylboronic acid (0.61 g, 4 mmol), Pd(PPh₃)₄ (116 mg, 0.1mmol) and potassium carbonate (560 mg, 4 mmol) were dissolved in amixture of DME (18 mL) and H₂O (2 mL) and degassed for 15 min with Ar(g). The reaction mixture was then heated at 84° C. for 18 h. At thistime, a further 0.25 eq. of 3-methoxyphenylboronic acid (0.15 g, 1 mmol)was added and heating was continued. After a total of 42 h, the reactionmixture was cooled to rt, H₂O (40 mL) and EtOAc (40 mL) were added andthe reaction mixture shaken, the EtOAc layer was separated and theaqueous layer shaken with EtOAc (2×30 mL). The combined organic layerswere dried over Na₂SO₄ and concentrated to a yellow oil. This waspurified by liquid chromatography on silica gel eluting withEtOAc:hexane (3:7) to afford a white solid that was further purified bypreparative HPLC to afford2-[3-(3-methoxyphenyl)-1H-pyrrol-1-yl]pyridine as a white solid. ¹H NMR(CD₃Cl, 300 MHz) δ 8.52-8.54 (1H, m), 7.55 (1H, ddd), 7.38-7.39 (1H, m),7.15-7.21 (2H, m), 6.76-6.85 (4H, m), 6.46-6.48 (1H, m), 6.41 (1H, dd).MS (ESI) 251 (M+H)⁺.

COMPOUND 2 Synthesis of 3-iodo-1-(triisopropylsilyl)-1H-pyrrole

3-Iodo-1-(triisopropylsilyl)-1H-pyrrole was prepared according to themethod of Bray, B. L. et al. J. Org. Chem. 1990, 55, 6317-6328.

COMPOUND 3 Synthesis of 2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]pyridine

A solution of 3-iodo-1-(triisopropylsilyl)-1H-pyrrole (11.0 g, 2.87mmol), triphenylphosphine (27 mg, 0.103 mmol), andtetrakis(triphenylphosphine)palladium(0) (80 mg, 0.069 mmol) in THF (20mL) was degassed with Ar (g) for 15 min, then 2-bromo(pyridin-2-yl)zinc(1.5 mL of 0.5M solution, 5.74 mmol) was added and degassing continued afurther 15 min. The reaction was stirred at 70° C. for 5 h and monitoredby LC/MS. The reaction mixture was quenched with H₂O (40 mL) thenextracted with EtOAc (3×25 mL) and the combined organic extracts washedwith brine. The organic phase was dried over Na₂SO₄, concentrated invacuo and the crude residue was chromatographed on silica gel elutingwith EtOAc:hexane (1:9) to afford2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]pyridine as a clear oil whichwas used below without further purification.

COMPOUND 4 Synthesis of 2-(1H-pyrrol-3-yl)pyridine

To a solution of 2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]pyridine (1 g,3.2 mmol) in anhydrous THF (15 mL) was added TBAF (3.84 mL of a 1Msolution in THF, 3.84 mmol). After stirring for 10 min. at rt, thereaction was complete. The reaction mixture quenched with H₂O (40 mL),extracted with EtOAc (3×25 mL) and the combined organic extracts washedwith brine. The organic phase was dried over Na₂SO₄, concentrated invacuo and chromatographed on silica gel eluting with EtOAc:hexane (1:1)to afford 2-(1H-pyrrol-3-yl)pyridine as a solid. ¹H NMR (CD₃Cl, 300 MHz)δ 8.55 (ddd, 1H), 7.65 (dt, 1H), 7.54 (dd, 1H), 7.46˜7.43 (d, 1H), 7.07(ddd, 1H), 6.85 (dd, 1H), 6.74 (dd, 1H). MS (ESI) 145.1 (M⁺+H).

EXAMPLE 4 Synthesis of 3-(3-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile

2-(1H-Pyrrol-3-yl)pyridine (0.144 g, 11.0 mmol), 3-fluorobenzonitrile(1.21 g, 10 mmol), and potassium carbonate (0.0.276 g, 2 mmol) wereheated at 145° C. in DMF (0.5 mL) for 14 h. After this time, thereaction mixture was cooled to rt and quenched with H₂O (30 mL). Themixture was extracted with EtOAc (3×25 mL) and the combined organicextracts washed with brine. The organic phase was dried over Na₂SO₄,concentrated in vacuo and the residue was chromatographed on silica geleluting with EtOAc:hexane (2:3) to afford a white solid which wasrecrystallized from dichloromethane-hexane to give3-(3-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile as white crystals. ¹H NMR(CD₃Cl, 300 MHz) δ 8.59 (ddd, 1H), 7.78˜7.71 (m, 3H), 7.68 (dd, 1H),7.62˜7.53 (m, 3H), 7.17˜7.11 (m, 2H), 6.89 (dd, 1H). MS (ES) 246.1(M⁺+H).

EXAMPLE 5 Synthesis of2-{1-[3-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl}pyridine hydrochloride

Following the procedure described in EXAMPLE4,2-(1H-pyrrol-3-yl)pyridine (0.072 g, 0.50 mmol),1-fluoro-3-(trifluoromethyl)benzene (0.82 g, 5.0 mmol), and potassiumcarbonate (0.138 g, 1.0 mmol) were employed to obtain2-{1-[3-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl}pyridine hydrochlorideas an orange solid. ¹H-NMR (CD₃OD, 300 MHz) 8.60 (d, 1H), 8.49-8.46 (m,2H), 8.36 (d, 1H), 7.98-7.94 (m, 2H), 7.80-7.71 (m, 3H), 7.62 (t, 1H),7.13 (dd, 1H). MS (EI) 289.0 (M⁺+H).

EXAMPLE 6 Synthesis of 2-[1-(3,5-dichlorophenyl)-1H-pyrrol-3-yl]pyridinehydrochloride

A solution of 2-(1H-pyrrol-3-yl)pyridine (0.072 g, 0.5 mmol),1,3-dichloro-5-iodobenzene (0.163 g, 0.6 mmol), 1,10-phenanthroline(0.360 g, 2 mmol) and potassium phosphate (0.223 g, 1.05 mmol) indioxane were degassed for 10 min, then copper (I) iodide (0.038 g, 0.2mmol) was added and the mixture degassed a further 10 min. The mixturewas heated to 110° C. for 4 h. The reaction mixture was quenched withbrine, extracted with EtOAc (3×25 mL) and the combined organic extractswashed with brine. The organic phase was dried over Na₂SO₄, concentratedin vacuo and the residue was chromatographed on silica gel eluting withEtOAc:hexane (1:4) to afford a white solid. The crude material wasdissolved in THF (5 mL), 1.2 eq. of 1M HCl in diethyl ether was addedand the resulting precipitate was filtered to obtain2-[1-(3,5-dichlorophenyl)-1H-pyrrol-3-yl]pyridine hydrochloride as awhite solid. ¹H-NMR (CD₃OD, 300 MHz) δ 8.60 (d, 1H), 8.50 (dd, 1H), 8.41(dd, 1H), 8.34 (d, 1H), 7.80-7.69 (m, 3H), 7.59 (dd, 1H), 7.50-7.49 (m,1H), 7.11-7.09 (dd, 1H). MS (ESI) 289.0 (M⁺+H).

EXAMPLE 7 Synthesis of 2-[1-(3-methylphenyl)-1H-pyrrol-3-yl]pyridinehydrochloride

Following the procedure described in EXAMPLE6,2-(1H-pyrrol-3-yl)pyridine (0.072 g, 0.50 mmol) 1-iodo-3-methylbenzene(0.130 g, 0.6 mmol), 1,10-phenanthroline (0.360 g, 2 mmol) and potassiumphosphate (0.223 g, 1.05 mmol) and copper (I) iodide (0.038 g, 0.2 mmol)were employed to obtain 2-[1-(3-methylphenyl)-1H-pyrrol-3-yl]pyridine.Treatment of this material with 1.2 eq. of 1M HCl in diethyl etherprovided 2-[1-(3-methylphenyl)-1H-pyrrol-3-yl]pyridine hydrochloride asa white solid. ¹H-NM (CD₃OD, 300 MHz) δ 8.46 (d, 1H), 8.35 (dd, 1H),8.24-8.20 (m, 21), 7.65-7.60 (m, 1H), 7.41-7.38 (m, 2H), 7.34-7.32 (m,2H), 7.17-7.14 (m, 1H), 6.97 (dd, 1H), 2.37 (s, 3H). MS (ESI) 235.3(M⁺+H).

EXAMPLE 8 Synthesis of 2-[1-(3-methoxyphenyl)-1H-pyrrol-3-yl]pyridinehydrochloride

Following the procedure described in EXAMPLE6,2-(1H-pyrrol-3-yl)pyridine (0.072 g, 0.50 mmol)1-bromo-3-methoxybenzene (0.113 g, 0.6 mmol), 1,10-phenanthroline (0.360g, 2 mmol) and potassium phosphate (0.223 g, 1.05 mmol) and copper (I)iodide (0.038 g, 0.2 mmol) were employed to obtain2-[1-(3-methoxyphenyl)-1H-pyrrol-3-yl]pyridine. Treatment of thismaterial with 1.2 eq. of 1M HCl in diethyl ether provided2-[1-(3-methoxyphenyl)-1H-pyrrol-3-yl]pyridine hydrochloride as a whitesolid. ¹H-NMR (CD₃OD, 300 MHz) δ 8.55 (d, 1H), 8.45 (dd, 1H), 8.33-8.29(m, 2H), 7.74-7.69 (m, 1H), 7.51 (dd, 1H), 7.48-7.42 (m, 1H), 7.21-7.17(m, 2H), 7.04 (dd, 1H), 7.00-6.97 (m, 1H), 3.89 (s, 3H). MS (ESI) 251.1(M⁺+H).

COMPOUND 5 Synthesis of2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]-1,3-thiazole

To a solution of 3-bromo-1-(triisopropylsilyl)-1H-pyrrole (0.691 g, 2.28mmol) in THF (10 mL) at −78° C. was added t-butyllithium (2.83 mL, 4.80mmol of 1.7M solution in heptane). The solution was stirred at −78° C.for 45 min, then trimethylborate (2.38 g, 22.8 mmol) was added andstirred at −78° C. for 20 min. The reaction mixture was allowed to warmto rt and then cooled again to −78° C. before methanol:water (V:V=1:1,0.9 mL) was added and the solution allowed warm to rt. The reactionmixture was quenched with brine (10 mL) and extracted with EtOAc (3×25mL). The combined organic phase was washed with brine, dried over Na₂SO₄and concentrated in vacuo to give crude1-(triisopropylsilyl)-1H-pyrrol-3-ylboronic acid which was used withoutfurther purification.

A solution of crude 1-(triisopropylsilyl)-1H-pyrrol-3-ylboronic acid,2-bromo-1,3-thiazole (0.206 g, 1.26 mmol) and potassium carbonate (0.174g, 1.26 mmol) in benzene (10 mL), methanol (1 mL) and water (1 mL) wasdegassed with argon for 15 min. Tetrakis(triphenylphosphine)palladium(0)(40 mg, 0.034 mmol) was added and the reaction mixture was degassed afurther 15 min before stirring at 70° C. for 14 h. The reaction mixturewas quenched with water (30 mL) then extracted with EtOAc (3×30 mL) andwashed with brine. The combined organic phase was dried over Na₂SO₄ andconcentrated in vacuo. The crude residue was chromatographed on silicagel eluting with EtOAc:hexane (1:1) to afford2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]-1,3-thiazole as a brown oil. ¹HNMR (CD₃Cl, 300 MHz) δ 7.68 (d, 1H), 7.37-7.36 (m, 1H), 7.08 (d, 1H),7.76-7.75 (m, 1H), 6.70 (dd, 1H), 1.46 (h, 3H) 1.09 (d, 18H).

COMPOUND 6 Synthesis of 2-(1H-pyrrol-3-yl)-1,3-thiazole

To a solution of 2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]-1,3-thiazole(0.200 g, 0.671 mmol) in anhydrous THF (2 mL) was added TBAF (1 mL, 1mmol of a 1M in THF) and after stirring for 20 min at rt, the reactionwas complete. The reaction mixture was quenched with water (40 mL),extracted with EtOAc (3×25 mL) and washed with brine. The organic phasewas dried over Na₂SO₄, concentrated in vacuo and chromatographed onsilica gel eluting with EtOAc:hexane (1:1) to afford2-(1H-pyrrol-3-yl)-1,3-thiazole as a pale solid. ¹H NMR (CD₃Cl, 300 MHz)δ 8.20 (br, 1H) 7.63 (d, 1H), 7.28 (d, 1H), 7.06 (d, 1H), 6.73 (dd, 1H),6.57 (dd, 1H).

EXAMPLE 9 Synthesis of3-[3-(1,3-thiazol-2-yl)-1H-pyrrol-1-yl]benzonitrile

Following the procedure described in EXAMPLE4,2-(1H-pyrrol-3-yl)-1,3-thiazole (0.100 g, 0.66 mmol),1-fluoro-3-(trifluoromethyl)benzene (0.805 g, 6.66 mmol), and potassiumcarbonate (0.183 g, 1.33 mmol) were employed to obtain3-[3-(1,3-thiazol-2-yl)-1H-pyrrol-1-yl]benzonitrile. Treatment of thismaterial with 1.2 eq. of 1M HCl in diethyl ether provided3-[3-(1,3-thiazol-2-yl)-1H-pyrrol-1-yl]benzonitrile hydrochloride as apale solid. ¹H-NMR (CD₃OD, 300 MHz) δ 8.42 (t, 1H), 8.14-8.11 (m, 2H),8.03-7.97 (m, 1H), 7.90 (m, 1H), 7.81-7.71 (m, 2H), 7.63 (dd, 1H), 7.03(d, 1H). MS (ESI) 252.1 (M⁺+H).

EXAMPLE 10 to EXAMPLE 22 shown below were prepared similarly to theschemes and procedures described above (ND=not determined).

Example Structure ¹H NMR MS (ESI) NAME 10

8.58-8.57 (dd, 1H),7.74-7.73 (m, 1H),7.69-7.66 (m, 1H),7.56 (br, 1H),7.53-7.51 (d, 1H), 7.45-7.42 (m, 1H), 7.26-7.24 (m, 1H), 7.13-7.11 (m,2H), 6.89-6.88 (m, 1H). MS 265.1(M⁺ + H).3-fluoro-5-(3-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile 11

8.62-8.61 (d, 1H),7.99-7.98 (d, 1H),7.77-7.73 (m, 1H),7.69-7.68 (d,1H),7.54 (s, 1H), 7.43-7.41 (m, 1H), 7.30-7.28 (m, 1H), 7.227.20 (m,2H). MS 342.15(M⁺ + H).3-(3-bromo-4-pyridin-2-yl-1H-pyrrol-1-yl)-5-fluorobenzonitrile 12

8.62-8.61 (m, 1H),7.71-7.67 (m, 1H),7.58-7.57 (d, 1H),7.51-7.49 (m,2H),7.39-7.36 (m, 1H),7.20-7.18 (m, 1H),7.15-7.13 (m, 1H),6.934-6.927(m,1H), 2.39 (s, 1H). MS 278.61(M⁺ + H).3-fluoro-5-(3-methyl-4-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile 13

8.68-8.67 (d, 1H),7.82-7.80 (d, 1H),7.75-7.71 (m, 1H),7.58 (s, 1H),7.48-7.43 (m, 2H), 7.20-7.17 (m, 1H),6.934-6.928 (d,1H), 6.90-6.89 (d,1H). MS 298.33(M⁺ + H).3-(3-chloro-4-pyridin-2-yl-1H-pyrrol-1-yl)-5-fluorobenzonitrile 14

7.74 (d, 1H), 7.66(d, 1H), 7.51 (s,1H), 7.37-7.40 (m,2H), 7.26 (m,1H),7.10 (dd, 1H), 6.63(m, 1H), 6.42 (dd, 1H). MS 253.3(M⁺ + H).3-fluoro-5-[3-(1H-pyrazol-1-yl)-1H-pyrrol-1-yl]benzonitrile 15

8.59 (d, 1H), 8.13(dd, 1H), 7.74 (dd,1H), 7.68 (m, 1H),7.56-7.61 (m,2H),7.31 (d, 1H), 7.16(d, 1H), 7.12 (m,1H), 6.88 (m, 1H). MS 256.4(M⁺ +H). 2-chloro-6-(3-pyridin-2-yl-1H-pyrrol-1-yl)pyridine 16

N/A MS 315.3(M⁺ + H).2-(pyridin-3-yloxy)-6-(3-pyridin-2-yl-1H-pyrrol-1-yl)pyridine 17

8.57 (d, 1H), 8.09(m, 1H), 7.66 (m,1H), 7.54-7.58 (m,2H), 7.08-7.11(m,2H), 6.99 (s, 1H),6.84 (dd, 1H), 2.40(s, 3H). MS 270.7(M⁺ + H).2-chloro-4-methyl-6-(3-pyridin-2-yl-1H-pyrrol-1-yl)pyridine 18

8.87-8.86 (d, 1H),8.65-8.66 (d, 1H),8.44-8.46 (m, 1H),8.27-8.30 (m,3H),8.03 (s, 1H), 7.85(s, 1H), 7.70-7.72(m, 1H), 7.39(s, 1H). MS280.1(M⁺ + 2H). 3-chloro-5-(3-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile19

8.87 (s, 1H), 8.70-8.71 (d, 1H), 8.59-8.60 (d, 1H), 8.55-8.50 (m, 2H),8.39-8.41 (d, 1H), 8.34-8.36 (d, 1H)8.12-8.14 9 (m, 1H),7.76-7.78 (m,1H),7.62 (s, 1H), 7.53(s, 1H), 7.51 (s,1H), 7.10-7.14 (m, 2H) MS333.1(M⁺ + 1H).2-{1-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-1H-pyrrol-3-yl}pyridine 20

8.61-8.62 (d, 1H),8.50-8.53 (m, 1H),8.40-8.41(m, 1H),8.35-8.36 (d,1H),7.9-7.81 (m, 2H),7.61-7.62 (m, 1H),7.54-7.57 (d, 1H),7.42-7.46 (d,1H),7.11-7.12 (m, 1H). MS 319.0(M⁺ + 2H).3-bromo-5-(3-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile 21

8.56-8.57 (d, 1H),7.73-7.74 (d, 1H),7.65-7.68 (m, 1H),7.51-7.54 (m,3H),7.36 (s, 1H), 7.09-7.12(m, 2H), 6.84-6.86 (m, 1H). MS 259.3(M⁺ + H).3-methyl-5-(3-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile 22

8.79-8.78 (d, 1H), 7.674-7.666 (m,1H), 8.5 (s, 1H),7.44-7.41 (m,1H),7.31-7.29 (m, 1H),7.25-7.24 (d, 1H),7.13-7.12 (m, 1H),6.855-6.846(m, 1H). MS 252.1(M⁺ + H).3-fluoro-5-[3-(1,3-thiazol-2-yl)-1H-pyrrol-1-yl]benzonitrile

Other variations or modifications, which will be obvious to thoseskilled in the art, are within the scope and teachings of thisinvention. This invention is not to be limited except as set forth inthe following claims.

1. A compound of the Formula (I):

wherein: X and Y each independently is aryl or heteroaryl wherein atleast one of X and Y is a heteroaryl with N adjacent to the position ofattachment to A or B respectively; X is optionally substituted with 1-7independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl,—OR¹, —NR¹R², —C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO²R²,—NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹,—CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionallytwo substituents are combined to form a cycloalkyl or heterocycloalkylring fused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups; R¹, R²,and R³ each independently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, oraryl; any of which is optionally substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, ——O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents; R⁴ is C₁₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; optionally substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents; A is —C₀₋₄alkyl,—C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—C₀₋₂alkyl-CO—C₀₋₂alkyl-, —C₀₋₂alkyl-NR⁹CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR⁹SO₂-C₀₋₂alkyl or heteroC₀₋₄alkyl; Y is optionallysubstituted with 1-7 independent halogen, —CN, NO₂, —C₁₋₆alkyl,—C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR⁵, —NR⁵R⁶, —C(═NR⁵)NR⁶R⁷, —N(═NR⁵)NR⁶R⁷,—NR⁵COR⁶, —NR⁵CO₂R⁶, —NR⁵SO₂R⁸, —NR⁵CONR⁶R⁷, —SR⁸, —SOR⁸, —SO₂R⁸,—SO₂NR⁵R⁶, —COR⁵, —CO₂R⁵, —CONR⁵R⁶, —C(═NR⁵)R⁶, or—C(═NOR⁵)R⁶substituents, wherein optionally two substituents arecombined to form a cycloalkyl or heterocycloalkyl ring fused to Y;wherein the C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),or —N(C₀₋₆alkyl)(aryl) groups; R⁵, R⁶, and R⁷ each independently is—C₀₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; any of which isoptionally substituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents; R⁸is —C₁₋₆alkyl, —C₃₋₇cycloalkyl,heteroaryl, or aryl; optionally substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents; B is —C₀₋₄alkyl,—C₀₋₂alkyl-SO—C₀₋₂alkyl-, —C₀₋₂alkyl-SO₂—C₀₋₂alkyl-,—CO₂alkyl-CO—C₀₋₂alkyl-, C₀₋₂alkyl-NR¹⁰CO—C₀₋₂alkyl-,—C₀₋₂alkyl-NR¹⁰SO₂C₀₋₂alkyl or heteroC₀₋₄alkyl; R⁹ and R¹⁰ eachindependently is —C₀₋₆alkyl, —C₃₋₇cycloalkyl, heteroaryl, or aryl; anyof which is optionally substituted with 1-5 independent halogen, —CN,—C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),—N(C₀₋₆alkyl)(aryl) substituents; R¹¹, R¹² and R¹³ is each independentlyhalogen, —C₀₋₆alkyl, —C₀₋₆alkoxyl, ═O, ═N(C₀₋₄alkyl),or—N(C₀₋₄alkyl)(C₀₋₄alkyl), wherein optionally two of R¹¹, R¹² and R¹³ arecombined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ringfused to the pyrrole moiety; wherein the —C₁₋₆alkyl substituent,cycloalkyl ring, or heterocycloalkyl ring each optionally is furthersubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups; any N may be an N-oxide; and wherein any ofthe alkyl optionally is substituted with 1-9 independent halogens; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1wherein: X is 2-pyridyl optionally substituted with 1-4 independenthalogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups.
 3. Thecompound of claim 2 wherein: Y is phenyl optionally substituted with 1-5independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl,—OR¹, —NR¹R², —C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R²,—NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹,—CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R² substituents, wherein optionallytwo substituents are combined to form a cycloalkyl or heterocycloalkylring fused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups.
 4. Thecompound of claim 1 wherein: Y is 2-pyridyl optionally substituted with1-4 independent halogen, —CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl,—C₁₋₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR²,—NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R²,—COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R² substituents,wherein optionally two substituents are combined to form a cycloalkyl orheterocycloalkyl ring fused to Y; wherein the —C₁₋₆alkyl substituent,cycloalkyl ring, or heterocycloalkyl ring each optionally is furthersubstituted with 1-5 independent halogen, —CN, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups.
 5. The compound of claim 4 wherein: X ispyridyl optionally substituted with 1-4 independent halogen, —CN, NO₂,—C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, 1, NR¹R², —C(═NR¹)NR²R³,—N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴,—SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R², —C(NR¹)R², or—C(═NOR¹)R²substituents, wherein optionally two substituents arecombined to form a cycloalkyl or heterocycloalkyl ring fused to X;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),or —N(C₀₋₆alkyl)(aryl) groups.
 6. The compound of claim 1 wherein: X isphenyl optionally substituted with 1-5 independent halogen, —CN, NO₂,—C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³,—N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R₂, —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴,—SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or—C(═NOR¹)R²substituents, wherein optionally two substituents arecombined to form a cycloalkyl or heterocycloalkyl ring fused to X;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),or —N(C₀₋₆alkyl)(aryl) groups.
 7. The compound of claim 6 wherein: Y is2-pyridyl optionally substituted with 1-4 independent halogen, —CN, NO₂,—C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³,—N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴,—SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or—C(═NOR¹)R²substituents, wherein optionally two substituents arecombined to form a cycloalkyl or heterocycloalkyl ring fused to Y;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —Cn, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),or —N(C₀₋₆alkyl)(aryl) groups.
 8. The compound of claim 1 wherein: Y is1,3-thiazol-2-yl optionally substituted with 1-2 independent halogen,—CN, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R²,—C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R², —NR¹SO₂R⁴,—NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R²,—C(═NR¹)R², or —C(═NOR¹)R²substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to Y; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —Cn, C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups.
 9. Thecompound of claim 8 wherein: X is phenyl optionally substituted with 1-5independent halogen, —Cn, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl,—OR¹, —NR¹R², —C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR², —NR¹CO₂R²,—NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹,—CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R²substituents, wherein optionally twosubstituents are combined to form a cycloalkyl or heterocycloalkyl ringfused to X; wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, orheterocycloalkyl ring each optionally is further substituted with 1-5independent halogen, —CN, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl),—O(aryl), —O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl),—N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or —N(C₀₋₆alkyl)(aryl) groups.
 10. Thecompound of claim 1 wherein: Y is pyrazolyl optionally substituted with1-3 independent halogen, —Cn, NO₂, —C₁₋₆alkyl, —C₁₋₆alkenyl,—C₁₋₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³, —N(═NR¹)NR²R³, —NR¹COR²,—NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR¹R²,—COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or —C(═NOR¹)R²substituents, whereinoptionally two substituents are combined to form a cycloalkyl orheterocycloalkyl ring fused to Y; wherein the —C₁₋₆alkyl substituent,cycloalkyl ring, or heterocycloalkyl ring each optionally is furthersubstituted with 1-5 independent halogen, —Cn, —C₁₋₆alkyl,—O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl), —O(heteroaryl),—N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl), or—N(C₀₋₆alkyl)(aryl) groups.
 11. The compound of claim 10 wherein: X isphenyl optionally substituted with 1-5 independent halogen, —Cn, NO₂,—C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl, —OR¹, —NR¹R², —C(═NR¹)NR²R³,—N(═NR¹)NR²R³, —NR¹COR₂, —NR¹CO₂R², —NR¹SO₂R⁴, —NR¹CONR²R³, —SR⁴, —SOR⁴,—SO₂R⁴, —SO₂NR¹R², —COR¹, —CO₂R¹, —CONR¹R², —C(═NR¹)R², or—C(═NOR¹)R²substituents, wherein optionally two substituents arecombined to form a cycloalkyl or heterocycloalkyl ring fused to X;wherein the —C₁₋₆alkyl substituent, cycloalkyl ring, or heterocycloalkylring each optionally is further substituted with 1-5 independenthalogen, —Cn, —C₁₋₆alkyl, —O(C₀₋₆alkyl), —O(C₃₋₇cycloalkyl), —O(aryl),—O(heteroaryl), —N(C₀₋₆alkyl)(C₀₋₆alkyl), —N(C₀₋₆alkyl)(C₃₋₇cycloalkyl),or —N(C₀₋₆alkyl)(aryl) groups.
 12. A compound which is selected from thegroup consisting of: 3-(1-pyridin-2-yl-1H-pyrrol-3-yl)benzonitrile;2-[3-(3-chiorophenyl)-1H-pyrrol-1-yl]pyridine;2-[3-(3-methoxyphenyl)-1H-pyrrol-1-yl]pyridine;3-(3-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile;2-{1-[3-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl}pyridine;2-[1-(3,5-dichiorophenyl)-1H-pyrrol-3-yl]pyridine;2-[1-(3-methylphenyl)-1H-pyrrol-3-yl]pyridine;2-[1-(3-methoxyphenyl)-1H-pyrrol-3-yl]pyridine;3-[3-(1,3-thiazol-2-yl)-1H-pyrrol-1-yl]benzonitrile;3-fluoro-5-(3-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile;3-(3-bromo-4-pyridin-2-yl-1H-pyrrol-1-yl)-5-fluorobenzonitrile;3-fluoro-5-(3-methyl-4-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile;3-(3-chloro-4-pyridin-2-yl-1H-pyrrol-1-yl)-5-fluorobenzonitrile;3-fluoro-5-[3-(1H-pyrazol-1-yl)-1H-pyrrol-1-yl]benzonitrile;2-chloro-6-(3-pyridin-2-yl-1H-pyrrol-1-yl)pyridine;2-(pyridin-3-yloxy)-6-(3-pyridin-2-yl-1H-pyrrol-1-yl)pyridine;2-chloro-4-methyl-6-(3-pyridin-2-yl-1H-pyrrol-1-yl)pyridine;3-chloro-5-(3-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile;2-{1-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-1H-pyrrol-3-yl}pyridine;3-bromo-5-(3-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile;3-methyl-5-(3-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile;3-fluoro-5-[3-(1,3-thiazol-2-yl)-1H-pyrrol-1-yl]benzonitrile; or apharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition comprising the compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 14.A pharmaceutical composition comprising the compound of claim 12, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 15. A method of treatment or prevention of paincomprising the step of administering a therapeutically effective amountor a prophylactically effective amount of the compound of claim 1 or apharmaceutically acceptable salt thereof.
 16. A method of treatment orprevention of a pain disorder wherein the pain disorder is acute pain,persistent pain, chronic pain, inflammatory pain or neuropathic pain,comprising administering a therapeutically effective amount or aprophylactically effective amount of the compound of claim 1 or apharmaceutically acceptable salt thereof.